TNF-α (tumor necrosis factor), a member of cytokine family, was discovered to be a substance which has cell death inducing activity and cell proliferation inhibiting activity against tumor cells. Thereafter it has been reported that TNF-α can be produced by monocyte or macrophage stimulated by lipopolysaccharide and the like, which plays a key role in the inflammation or immunoreaction. Moreover, it has been revealed that TNF-α has a wide variety of biological activities on greatly different types of cell in addition to tumor cell, including the activation of macrophage and neutrophile, the expression of adhesive molecules in the endothelial cell, the increased proliferation of fibroblast cells, the activation of human immune deficiency virus (HIV-1) gene in CD4 positive cell and macrophage, and the like (Nature, vol. 320, 1986, pp 584-588).
IL-6, a member of cytokine family, was discovered to be a substance which promotes the differentiation of B cell into antibody producing cell without showing any effect on B cell proliferation and which is secreted in the culture supernatant of T cell stimulated with mitogen. Then, it was reported that IL-6 was produced when T cell as well as monocytes, macrophage and the like were stimuleted with cytokines such as lipopolysaccharide, TNF, IL-1 and the like. Moreover, it has been revealed that IL-6 has a wide variety of biological activities on greatly different types of cell in addition to B cell including the production of acute phase reactive protein in hepatic cell, the promotion of osteoclast bone resorption, the increase in platelet number and the like (Blood, vol. 7, 1989, pp 1-10).
IL-2, a member of cytokine family, is known as a T cell proliferation factor. IL-2 was mainly produced by T cell and to some extent by NK cell. Induced production of interferon γ in T or NK cell by IL-2 has an important rule in the formation of cytokine network.
TNF-α has been shown to be involved in the exacerbation and progression of diseased conditions including chronic rheumatoid arthritis, osteoarthritis, sepsis, Crohn's disease, diabetes mellitus, fulminant hepatitis, cachexia due to end-stage cancer and the like. IL-6 was been shown to be involved in the exacerbation and progression of diseased conditions including chronic rheumatoid arthritis, atrial myxoma, Castleman's syndrome, multiple myeloma, hyper gamma-globulinemia in present individuals with AIDS and the like. Steroids have been previously known to a substance which can inhibit TNF-α, IL-6 and IL-2. Their effects have been definitely appreciated, but there has been a problem of serious side effects following their prolonged use. Additionally, clinical applications of anti-TNF-α antibody, anti-IL-6 antibody and anti-IL-2 antibody have been investigated mainly for the treatment of chronic rheumatoid arthritis. Their effects have been appreciated, but there have been problems of the limitation that they can be used only for injection, the appearance of antibodies against anti-TNF-α antibody, anti-IL-6 antibody and anti-IL-2 antibody following continuous use leading to decreased effectiveness, expensiveness to formulate them into therapeutic drugs and the like. Therefore, it is expected that exploration of lower molecular weight compounds to inhibit the production of TNF-α, IL-6 and IL-2 results in the development of useful drugs which can be replaced for steroids and antibody formulations for the treatment of these diseases.